Resveratrol Improved Cognitive Degeneration In Chronic Cerebral Hypoperfusion Rats Via Reducing The Nuclear Translocation Of HDAC6

ObjectiveVascular dementia(VD)is a common disease in the elderly population,and chronic cerebral hypoperfusion is the main cause of VD,which is an important risk factor for Alzheimer’s disease as well.Donepezil,a FDA proved drug that treats early AD,can improve cognitive degeneration caused by VD,but the effects are limited.Resveratrol is a natural compound with superior antioxidant effect.It can be extracted from Chinese medicine polygonum cuspidatum,which can improve cardiovascular disease,delay senility and protect neuron.Although the clinical application of resveratrol is controversial,its biological activity deserves affirmation.In previous study,we found that donepezil was able to increase BDNF expression via reducing HDAC6 nuclear translocation in cerebral cortex of VD rats.By comparing the effect of resveratrol and donepezil on the improvement of cognitive dysfunction in rats with chronic cerebral hypoperfusion,this study explored the feasibility of resveratrol on the improvement of cognitive degeneration in rats with chronic cerebral hypoperfusion,providing a research basis for the further development and application of resveratrol.MethodsIn this study,bilateral common carotid artery occlusion(BCCAO)model rats were served to study neurodegeneration and cognitive degeneration caused by chronic cerebral ischemia.Resveratrol and donepezil were administered,respectively.Morris water maze experiment and step-down experiment were used to analyze the cognition and retention of the experimental rats.Nissl staining was used to detect neuron morphology,golgi staining was used to detect nerve dendritic spine density,and DHE staining was used to detect ROS generation.The distribution of HDAC6 was studied by immunofluorescence and further verified by detection of cytoplasmic and nuclear protein.The combination of BDNF promoter and HDAC6 was explored by ChIP.The expression levels of BDNF,p-AMPK/AMPK and p-AKT/AKT were detected by western blotting.In vitro,OGD/R PC 12 was treated with resveratrol and donepezil.The expression of nuclear HDAC6,cytoplasmic HDAC6,BDNF,p-AMPK/AMPK,and p-AKT/AKT were detected by western blotting.ResultsIn morris water maze experiment and step-down experiment,we found that both donepezil and resveratrol could improve the cognitive and memory dysfunction in rats with BCCAO.Through nissl staining,DHE staining and golgi staining,we found that resveratrol and donepezil could improve the morphology of nerve cells,reduce ROS,and enhance synaptic plasticity.Both resveratrol and donepezil increase the expression of BDNF in the brain,thereby protecting the nerves.Donepezil reduced cortical HDAC6 nuclear translocation and increased BDNF mRNA transcription,but had no effect in the hippocampus.In vitro,we treated PC 12 with OGD/R,which showed that both resveratrol and donepezil reduced HDAC6 nuclear translocation and increased BDNF mRNA expression.It was speculated that resveratrol could also protect nerve injury by reducing HDAC6 nuclear metastasis and thereby increasing BDNF mRNA transcription.ConclusionIn this study,compared with donepezil,resveratrol had a wider range of effects in the brain of BCCAO rats.Resveratrol could also inhibit HDAC6 translocation,activated the expression of p-AMPK/AMPK,and p-AKT/AKT,and thus increased the expression of BDNF,which suggesting that resveratrol has a better application prospect in the treatment of VD.